Human inhalation exposures to toluene, ethylbenzene, and m-xylene and physiologically based pharmacokinetic modeling of exposure biomarkers in exhaled air, blood, and urine. 2015

Axelle Marchand, and Rocio Aranda-Rodriguez, and Robert Tardif, and Andy Nong, and Sami Haddad
*Department of Environmental and Occupational Health, ESPUM, IRSPUM, Chair in Toxicological Risk Assessment and Management, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, and Exposure and Biomonitoring Division, Environmental Health Sciences and Research Bureau, Health Canada, 50 Columbine Driveway, Ottawa, Ontario, Canada K1A 0K9 *Department of Environmental and Occupational Health, ESPUM, IRSPUM, Chair in Toxicological Risk Assessment and Management, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, and Exposure and Biomonitoring Division, Environmental Health Sciences and Research Bureau, Health Canada, 50 Columbine Driveway, Ottawa, Ontario, Canada K1A 0K9.

Urinary biomarkers of exposure are used widely in biomonitoring studies. The commonly used urinary biomarkers for the aromatic solvents toluene (T), ethylbenzene (E), and m-xylene (X) are o-cresol, mandelic acid, and m-methylhippuric acid. The toxicokinetics of these biomarkers following inhalation exposure have yet to be described by physiologically based pharmacokinetic (PBPK) modeling. Five male volunteers were exposed for 6 h in an inhalation chamber to 1/8 or 1/4 of the time-weighted average exposure value (TWAEV) for each solvent: toluene, ethylbenzene, and m-xylene were quantified in blood and exhaled air and their corresponding urine biomarkers were measured in urine. Published PBPK model for parent compounds was used and simulations were compared with experimental blood and exhaled air concentration data. If discrepancies existed, Vmax and Km were optimized. Urinary excretion was modeled using parameters found in literature assuming simply stoichiometric yields from parent compound metabolism and first-order urinary excretion rate. Alternative models were also tested for (1) the possibility that CYP1A2 is the only enzyme implicated in o-cresol and (2) a 2-step model for describing serial metabolic steps for mandelic acid. Models adapted in this study for urinary excretion will be further used to interpret urinary biomarker kinetic data from mixed exposures of these solvents.

UI MeSH Term Description Entries
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D001944 Breath Tests Any tests done on exhaled air. Breathalyzer Tests,Breath Test,Breathalyzer Test,Test, Breath,Test, Breathalyzer,Tests, Breath,Tests, Breathalyzer
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D001555 Benzene Derivatives Organic compounds derived from BENZENE. Derivatives, Benzene
D014050 Toluene A widely used industrial solvent.
D014992 Xylenes A family of isomeric, colorless aromatic hydrocarbon liquids, that contain the general formula C6H4(CH3)2. They are produced by the destructive distillation of coal or by the catalytic reforming of petroleum naphthenic fractions. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Dimethylbenzenes,Xylene
D015415 Biomarkers Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, ENVIRONMENTAL EXPOSURE and its effects, disease diagnosis; METABOLIC PROCESSES; SUBSTANCE ABUSE; PREGNANCY; cell line development; EPIDEMIOLOGIC STUDIES; etc. Biochemical Markers,Biological Markers,Biomarker,Clinical Markers,Immunologic Markers,Laboratory Markers,Markers, Biochemical,Markers, Biological,Markers, Clinical,Markers, Immunologic,Markers, Laboratory,Markers, Serum,Markers, Surrogate,Markers, Viral,Serum Markers,Surrogate Markers,Viral Markers,Biochemical Marker,Biologic Marker,Biologic Markers,Clinical Marker,Immune Marker,Immune Markers,Immunologic Marker,Laboratory Marker,Marker, Biochemical,Marker, Biological,Marker, Clinical,Marker, Immunologic,Marker, Laboratory,Marker, Serum,Marker, Surrogate,Serum Marker,Surrogate End Point,Surrogate End Points,Surrogate Endpoint,Surrogate Endpoints,Surrogate Marker,Viral Marker,Biological Marker,End Point, Surrogate,End Points, Surrogate,Endpoint, Surrogate,Endpoints, Surrogate,Marker, Biologic,Marker, Immune,Marker, Viral,Markers, Biologic,Markers, Immune
D019570 Inhalation Exposure The exposure to potentially harmful chemical, physical, or biological agents by inhaling them. Exposure, Inhalation,Exposures, Inhalation,Inhalation Exposures

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